Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice.
| Title: | Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. |
|---|---|
| Authors: | Froese A; Cell and Developmental Biology, University of Würzburg, Würzburg, Germany.; Breher SS; Waldeyer C; Schindler RF; Nikolaev VO; Rinné S; Wischmeyer E; Schlueter J; Becher J; Simrick S; Vauti F; Kuhtz J; Meister P; Kreissl S; Torlopp A; Liebig SK; Laakmann S; Müller TD; Neumann J; Stieber J; Ludwig A; Maier SK; Decher N; Arnold HH; Kirchhof P; Fabritz L; Brand T |
| Source: | The Journal of clinical investigation [J Clin Invest] 2012 Mar; Vol. 122 (3), pp. 1119-30. Date of Electronic Publication: 2012 Feb 22. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 7802877 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1558-8238 (Electronic) Linking ISSN: 00219738 NLM ISO Abbreviation: J Clin Invest Subsets: MEDLINE |
| Imprint Name(s): | Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation; Original Publication: New Haven [etc.] American Society for Clinical Investigation. |
| MeSH Terms: | Cell Adhesion Molecules/*metabolism ; Muscle Proteins/*metabolism ; Potassium Channels, Tandem Pore Domain/*metabolism; Bradycardia/genetics ; Electrocardiography/methods ; Electrophysiology/methods ; Membrane Proteins/metabolism ; Telemetry/methods ; Animals ; Biological Clocks ; Heart Rate ; Mice ; Mice, Transgenic ; Phenotype ; Protein Structure, Tertiary ; Time Factors |
| Abstract: | Cardiac pacemaker cells create rhythmic pulses that control heart rate; pacemaker dysfunction is a prevalent disorder in the elderly, but little is known about the underlying molecular causes. Popeye domain containing (Popdc) genes encode membrane proteins with high expression levels in cardiac myocytes and specifically in the cardiac pacemaking and conduction system. Here, we report the phenotypic analysis of mice deficient in Popdc1 or Popdc2. ECG analysis revealed severe sinus node dysfunction when freely roaming mutant animals were subjected to physical or mental stress. In both mutants, bradyarrhythmia developed in an age-dependent manner. Furthermore, we found that the conserved Popeye domain functioned as a high-affinity cAMP-binding site. Popdc proteins interacted with the potassium channel TREK-1, which led to increased cell surface expression and enhanced current density, both of which were negatively modulated by cAMP. These data indicate that Popdc proteins have an important regulatory function in heart rate dynamics that is mediated, at least in part, through cAMP binding. Mice with mutant Popdc1 and Popdc2 alleles are therefore useful models for the dissection of the mechanisms causing pacemaker dysfunction and could aid in the development of strategies for therapeutic intervention. |
| Comments: | Comment in: J Clin Invest. 2012 Mar;122(3):810-3. doi: 10.1172/JCI62588.. (PMID: 22354173) |
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| Grant Information: | MR/J010383/1 United Kingdom MRC_ Medical Research Council |
| Molecular Sequence: | PDB 1CX4; 2PQQ |
| Substance Nomenclature: | 0 (Bves protein, mouse); 0 (Cell Adhesion Molecules); 0 (Membrane Proteins); 0 (Muscle Proteins); 0 (Popdc2 protein, mouse); 0 (Potassium Channels, Tandem Pore Domain); 0 (potassium channel protein TREK-1) |
| Entry Date(s): | Date Created: 20120223 Date Completed: 20120430 Latest Revision: 20250529 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC3287222 |
| DOI: | 10.1172/JCI59410 |
| PMID: | 22354168 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't